An estimated 1 billion people currently smoke tobacco, world-wide, and the World Health Organization forecasts cigarettes will kill nearly 9 million people per year globally by the year 2030. Epidemiological studies have shown that smokers suffer from more frequent infections and are at risk for more severe infectious complications than nonsmokers. However, there is surprisingly little understanding of tobacco smoke's specific impact on immune function and there is uncertainty about the mechanisms and full scope of its potential immunotoxicities. Given the prevalence of cigarette smoking (up to 1 out of 5 adults has smoked or is currently smoking in the U.S., CDC Statistics 2009) and health consequences from smoking, it is critical to determine whether tobacco smoke impairs the immune system. Therefore, our pilot project will begin to address the current lack of scientific understanding of the effects of tobacco smoke on the immune system response (specifically, both T and B cell activity) to vaccination in humans. Optimal responses to vaccination are associated with normal function of diverse components of the immune system (innate and adaptive, cellular and humoral). We will focus on effectiveness of vaccination against influenza vaccine. T cell activation is an important first step towards B cell-mediated synthesis of specific antibodies to vaccines. We hypothesize that tobacco smoke exposure decreases T cell and B cell function, thereby leading to impairment of cellular and humoral responses to the influenza vaccine. To test this hypothesis, we will study influenza vaccine responses (at baseline, 7-10 days and 24-32 days after vaccination). Monozygotic twins (MZT) will be studied (ages 16 to 55 yrs) who are discordant for smoking (i.e. ever smoked currently or historically vs. never smoked), n=30 (i.e. 15 pair; designated group A), vs. MZT concordant for smoking (i.e. ever smoked currently or historically), n=30 (group B), vs. MZT concordant for never smoking but within utero exposure to maternal smoke, n=30 (group C), vs. MZT concordant for never smoking and without in utero exposure to maternal smoke, n=30 (group D). The study design utilizes human samples to assess a broad array of advanced immunologic assays in relation to exposure to tobacco smoke. We will perform these cutting-edge functional measurements in blood using the services of the Human Immune Monitoring Center at Stanford to study global immune system changes, and to study specific T cell responses via tetramer-based assays and humoral responses to influenza vaccination. Thus, the global immune evaluation of influenza vaccine responses could serve as immune indicators of tobacco smoke toxicity. Overall, the results will be the basis for a more in-depth study to confirm and extend our work and to develop new strategies for biomonitoring of immune function and for identifying remediable environmental risk factors for prevalent conditions with substantial public health importance.